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Process for the preparation of sulphinyl derivatives by oxidation of the corresponding sulfides

a technology of sulphinyl derivatives and sulfides, which is applied in the field of process for preparing sufinyl derivatives, can solve the problems of limiting the industrial applicability of the process and being hardly applicable on industrial scal

Inactive Publication Date: 2006-01-19
CHEMI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this case the use of a toxic selenium catalyst, combined with that of halogenated solvents as reaction media, limits the industrial applicability of the process.
Unfortunately, even if this method is very good as regards selectivity, it is hardly applicable on industrial scale, both for the large quantities of very expensive catalyst employed and for the low temperatures at which the reaction has to be performed.
In fact, according to the above patent application, it is possible to achieve the good yields and the high purity of the final sulfoxide reported therein, only by keeping the amount of catalyst and the reaction temperature within specific values, rather disadvantageous from the industrial point of view.

Method used

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  • Process for the preparation of sulphinyl derivatives by oxidation of the corresponding sulfides
  • Process for the preparation of sulphinyl derivatives by oxidation of the corresponding sulfides
  • Process for the preparation of sulphinyl derivatives by oxidation of the corresponding sulfides

Examples

Experimental program
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Effect test

example 1

Synthesis of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridinyl]methyl]thio]-1H-benzimidazole (Lansoprazole sulfide, 1b)

[0046] To a stirred suspension of 100 g of 4-(2,2,2)-trifluoroethoxy-3-methyl-2-chloromethyl-pyridine hydrochloride and 54.4 g of 2-mercapto-benzimidazole at 10° C. in 500 ml of methanol, 125.6 g of a 30% by weight aqueous solution of NaOH are added at such a rate as to maintain the internal temperature within 35° C. The temperature of the mixture is then brought to 20÷25° C. and is kept for additional 4 hours in these conditions. Then 1000 ml of deionized water are added, causing the thickening of the precipitate. The pH of the suspension is adjusted to 9 with HCl 33% in water and the mixture is then cooled to 5° C. and maintained for 1 hour.

[0047] The precipitate obtained is filtered and washed with water to obtain 235 g of a wet product which once dried weighs 124.5 g and has an HPLC purity >99%. Yield 97%.

example 2

Synthesis of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (Lansoprazole, 2b)

[0048] In a 1-liter flask equipped with dropping funnel and mechanical stirring 50 g (0.142 moles) of Lansoprazole sulfide, 35.0 mg (0.00014 moles) of methyltrioxorhenium (Aldrich) and 500 ml of methanol are charged. The temperature of the solution is brought to 5° C., and then 17.8 g (0.173 moles) of a 33% (v / v) aqueous solution of hydrogen peroxide are added. The mixture is maintained at 5° C. for 4 hours, then 1000 ml of cold deionized water are added, whereby a dense precipitate forms. The mixture is stirred for 1 additional hour at 5° C. and is then filtered on a Buchner, the cake is washed with 3×100 ml of cold deionized water and is discharged. The wet solid weighs 59.5 g. A 1 g sample is collected and dried under vacuum (50 mmHg) at 40° C. for 12 hours, which loses 16.5% of its weight. The yield of crude product is thus 95%. The amount of residual water in th...

example 3

Synthesis of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (Lansoprazole, 2b)

[0049] The experiment described in example 1 was repeated on the same amount of sulfide, hydrogen peroxide and methanol, using 17.5 mg (0.00007 moles) of methyltrioxorhenium as catalyst.

[0050] After workup and crystallization, 39.0 g of the desired material (yield 74%, HPLC purity >99.5%) are obtained.

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Abstract

The present invention relates to a mild and industrially applicable process for preparing sulfinyl derivatives of Formula (II), useful as inhibitors of gastric acid secretion, comprising the selective oxidation of the corresponding sulfides of Formula (I), as represented in scheme (I) and (II) in which said oxidation is performed with hydrogen peroxide in the presence of low amounts of a rhenium compound as catalyst, at a temperature from 0° C. to room temperature.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a mild and industrially applicable process for preparing sufinyl derivatives, useful as inhibitors of gastric acid secretion, by selective oxidation of the corresponding sulfides, in particular by oxidation with hydrogen peroxide in the presence of a rhenium compound as catalyst BACKGROUND OF THE INVENTION [0002] A whole class of gastric Na / K pump inhibitors, widely used as antiulcer drugs, are benzimidazole compounds containing in their skeleton a sulfoxide moiety. Omeprazole, Lansoprazole, Pantoprazole and Rabeprazole are the most famous members of this class of compounds and several patents have appeared dealing with their synthesis. [0003] Whatever the staring materials are, the final step of their preparation is invariably the oxidation of the corresponding sulfide 1, as represented in the following Scheme 1: [0004] in which each substituent of the above formulae has, for the drugs just mentioned, the meaning repor...

Claims

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Application Information

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IPC IPC(8): A61K31/4439C07D403/02C07D401/12
CPCC07D401/12
Inventor TURCHETTA, STEFANOMASSARDO, PIETROTUOZZI, ANGELA
Owner CHEMI SPA
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